This project focuses upon a pathophysiologic study of bipolar disorder using olfactory receptor neurons (ORNs) from patients. ORNs, the only central nervous system (CNS) neurons that are obtainable through olfactory epithelial biopsy, can be a powerful tool for the molecular study of bipolar disorder. ORNs, accessible even multiple times in the same individuals, enables characterizing the neuronal pathology in a state- vs. trait dependent manner. Furthermore, since ORNs propagate in tissue culture condition, an in vitro cellular model of the illness can be developed. Recent molecular studies have implicated various abnormalities in signal transudation mechanisms and gene regulation in bipolar disorder. However, the pathophysiologic interpretation of these findings has been difficult, because it requires an examination of the proposed molecules in the neuronal tissues from patients in different phases of the illness. Recently, the investigators have investigated calcium homeostasis in ORNs from bipolar patients. The intracellular calcium responses in ORNs from 7 medication free euthymic bipolar patients were strikingly different than healthy control subjects. These suggest that ORNs from bipolar patients may express trait dependent intracellular abnormalities of the illness. In this study, characterization of the odorant induced intracellular calcium response in ORNs from depressed, hypomanic/or manic and euthymic bipolar patients are proposed. If the intracellular characteristics in vivo are maintained in vitro, cultured ORNs can be an in vitro model of the illness. To examine if the intracellular characteristics in vivo are maintained through time in tissue culture, odorant induced intracellular calcium responses will be characterized in cultured ORNs from euthymic patients, in comparison to acutely dissociated ORNs from the original tissue. ORNs provide a unique opportunity to characterize neuronal gene regulation in a state dependent vs. trait dependent manner. By applying single cell molecular techniques in conjunction with calcium imaging of odorant responsiveness, the investigators will be able to investigate gene regulation in functionally defined neurons from patients. In this proposal, the feasibility of amplifying anti-sense RNA from the ORNs after odorant responsiveness has been characterized by calcium imaging will be established.